Improving the inhibition of β-amyloid aggregation by withanolide and withanoside derivatives

Dubey, Shreya; Kallubai, Monika; Subramanyam, Rajagopal

doi:10.1016/j.ijbiomac.2021.01.094

Cited by 29Alzheimer's disease research and treatmentsPhytochemicals and Medicinal PlantsMedicinal Plants and Neuroprotection

Improving the inhibition of β-amyloid aggregation by withanolide and withanoside derivatives

Dubey, Shreya, Kallubai, Monika, Subramanyam, Rajagopal·2021·International Journal of Biological Macromolecules

DOI 10.1016/j.ijbiomac.2021.01.094

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Abstract

Here, we have studied the ameliorative effects of Withania somnifera derivatives (Withanolide A, Withanolide B, Withanoside IV, and Withanoside V) on the fibril formation of amyloid-β 42 for Alzheimer's disease. We analyzed reduction in the aggregation of β amyloid protein with these Ashwagandha derivatives by Thioflavin T assay in the oligomeric and fibrillar state. We have tested the cytotoxic activity of these compounds against human SK-N-SH cell line for 48 h, and the IC 50 value found to be 28.61 ± 2.91, 14.84 ± 1.45, 18.76 ± 0.76 and 30.14 ± 2.59 μM, respectively. After the treatment of the cells with half the concentration of IC 50 value, there was a remarkable decrease in the number of apoptotic cells stained by TUNEL assay indicating the DNA damage and also observed significant decrease of reactive oxygen species. Also, the binding and molecular stability of these derivatives with amyloid β was also studied using bioinformatics tools where these molecules were interacted at LVFFA region which is inhibition site of amyloid-β1 42. These studies revealed that the Withanolides and Withanosides interact with the hydrophobic core of amyloid-β 1-42 in the oligomeric stage, preventing further interaction with the monomers and diminishing aggregation.

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Withania somnifera derivatives (withanolide A, B, withanoside IV, V) have IC50 values of 28.61 ± 2.91, 14.84 ± 1.45, 18.76 ± 0.76, and 30.14 ± 2.59 μM on human SK N-SH cell line.
“The cytotoxic activity tested on the human SK N-SH cell line reported IC 50 value to be 28.61 ± 2.91, 14.84 ± 1.45, 18.76 ± 0.76, and 30.14 ± 2.59 µM, respectively.”
From Unlocking the Therapeutic Potential of Medicinal Plants for Alzheimer’s Disease: Preclinical to Clinical Trial Insights (2023) · cites this paper as [149]
Treatment with Withania somnifera derivatives reduces DNA damage and significantly decreases apoptotic cells.
“In addition, the tunnel assay showed reduced DNA damage and a significant decrease in apoptotic cells following treatment with WS derivatives.”
From Unlocking the Therapeutic Potential of Medicinal Plants for Alzheimer’s Disease: Preclinical to Clinical Trial Insights (2023) · cites this paper as [149]
Withania somnifera derivatives interact with hydrophobic core residues of β-amyloid, preventing binding of another β-amyloid peptide and preventing fibrillization.
“Additionally, molecular docking findings show that the derivatives interacted with the hydrophobic core residues area of -β amyloid, preventing the binding of another -β amyloid peptide and, therefore, preventing fibrillization.”
From Unlocking the Therapeutic Potential of Medicinal Plants for Alzheimer’s Disease: Preclinical to Clinical Trial Insights (2023) · cites this paper as [149]
Withanolide B and withanoside V complexes are stable inside hydrophobic core of β-amyloid in 100 ns simulations.
“Moreover, it appears from 100 ns simulations that the withanolide B and withanoside V complexes were stable inside the hydrophobic core of β-amyloid [149].”
From Unlocking the Therapeutic Potential of Medicinal Plants for Alzheimer’s Disease: Preclinical to Clinical Trial Insights (2023) · cites this paper as [149]

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Withania somnifera
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Authors: Dubey, S., Kallubai, M., & Subramanyam, R.
Affiliations: University of Hyderabad (IN)
Corresponding author: Subramanyam, Rajagopal
ORCID: Subramanyam, Rajagopal
Venue: International Journal of Biological Macromolecules
Publisher: Elsevier BV
Published: 2021-03
Volume: 173
Pages: 56-65
ISSN: 0141-8130 (ISSN-L)
DOI: 10.1016/j.ijbiomac.2021.01.094
OpenAlex: W3123061745
Cited by: 29
References: 44
Citations by year: 2026: 4 · 2025: 8 · 2024: 4 · 2023: 8 · 2022: 1 · 2021: 3 · 2017: 1
FWCI: 2.51
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: International Journal of Biological Macromolecules (publishedVersion)
PubMed (publishedVersion)
Funders: Science and Engineering Research Board (SB/EMEQ-064/2014 dated 14-07-2015)
Council of Scientific and Industrial Research, India
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Complementary and alternative medicine › Phytochemicals and Medicinal Plants
Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
Keywords: amyloid beta aggregation inhibition, Withania somnifera, withanolides, Alzheimer's disease, cytotoxicity, apoptosis, reactive oxygen species, protein-ligand binding, hydrophobic core, oligomeric amyloid, SK-N-SH cells
MeSH terms: Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Binding Sites, Cell Survival, Ergosterol, Humans, Neurons, Peptide Fragments, Plant Extracts, Protein Binding, Amyloid beta-Peptides, Neuroprotective Agents, Withania, Cell Line, Tumor, Withanolides, Protein Interaction Domains and Motifs, Molecular Dynamics Simulation, Molecular Docking Simulation, Protein Aggregates

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Improving the inhibition of β-amyloid aggregation by withanolide and withanoside derivatives

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